The goal of this research is to clarify the pathogenesis of diabetic retinopathy and to provide a rational basis for developing improved means to inhibit the retinopathy. The experiments described below are designed to investigate the role of one of the sequelae of hyperglycemia, nonenzymatic glycation, in the development of oxidative stress and other defects of retinal metabolism, and in the development of diabetic retinopathy. These studies will be conducted using experimentally diabetic dogs and rats, and for comparison, experimentally galactosemic rats. Dogs with diabetes develop retinal microaneurysms and other microvascular lesions identical to those characteristic of diabetic humans, and diabetes or galactosemia in rats results in at least the early stages of retinopathy. The potential role of AGEs in the etiology of (1) retinal dysmetabolism (initially focusing on oxidative stress) and of (2) the histopathology of diabetic retinopathy are to be investigated in long-term diabetic dogs, and in diabetic and galactosemic rats receiving aminoguanidine. Mechanisms which may account for protection of cerebral cortical microvessels from the lesions that develop characteristically in retinal microvessels in diabetes are to be investigated, with emphasis initially on comparing the two issues with respect to accumulation of AGEs and development of oxidative stress.